DESCRIPTION: Training Plan: The long-standing career goal of this candidate has been to apply the techniques of molecular biology to problems of viral pathogenesis. The mentored clinical scientist award offers the opportunity to have a focused four year research experience. This period will be used to explore new areas of virology and immunobiology. This experience will strengthen the candidate's potential to become a productive independent physician-scientist. The aim of the research project is to examine the role of the nef gene in the pathogenesis of the simian immunodeficiency virus (SIV). This work will be conducted at the New England Regional Primate Research Center of Harvard Medical School in the laboratory of Dr. Ronald Desrosiers. This is a productive, interactive environment in which the techniques of virology, protein biochemistry and immunology are practiced and taught. Specifically the effect of the SIV Nef protein on the process of signal transduction will be examined. The sequence requirements of the in vitro and in vivo phenotypes of SIV nef alleles will be addressed by site directed mutagenesis. The identification of the physiologically relevant cellular partners of the Nef protein will be attempted. The unique phenotype of a nef allele associated with an acute lymphoproliferative disease also will be further analyzed. This characterization of Nef and its cellular partners may enhance understanding of immunodeficiency virus pathogenesis, aide in the development of HIV vaccine models and provide new targets for the development of antiviral chemotherapy.